Opinions in hypertension. ARBs and risk of cancer: international and South African expert comment.

The suggestion from a recent meta-analysis that angiotensin receptor blockers (ARBs) are associated with an increase in new cancer occurrence but not cancer deaths, has resulted in the initiation of a safety review of this class of drugs by both the FDA (Federal Drug Administration) and the EMA (European Medicines Authority) in accordance with good regulatory practice. This was also advocated by Dr Steve Nissen in his editorial comment. In the interim, a review of the published meta-analysis plus input from Boehringer-Ingelheim is pertinent to clinical practice.

The suggestion from a recent meta-analysis that angiotensin receptor blockers (ARBs) are associated with an increase in new cancer occurrence but not cancer deaths, 1 has resulted in the initiation of a safety review of this class of drugs by both the FDA (Federal Drug Administration) and the EMA (European Medicines Authority) in accordance with good regulatory practice. This was also advocated by Dr Steve Nissen in his editorial comment. 2 In the interim, a review of the published meta-analysis plus input from Boehringer-Ingelheim is pertinent to clinical practice.

Meta-analysis of randomised control trials 1
This meta-analysis pooled the published randomised, controlled trials of ARBs and found that ARB use may be associated with a modest increased risk of new cancers -predominantly lung cancer. Patients who were randomly assigned to receive ARBs had an increased risk of new cancer occurrence compared with patients in the control groups (7.2 vs 6.0%, risk ratio 1.08, 95% CI, 1.01-1.15). When analysis was limited to those trials (LIFE, ONTARGET and TRANSCEND) where cancer was a pre-specified endpoint, the risk ratio was 1.11 (95% CI, 1.04-1.18, p = 0.001). The authors concluded that the findings of the meta-analysis warrant further investigation.
The meta-analysis reviewed 60 trials and included published and available FDA data from nine different trials (Table  1) to assess overall cancer risk and risk of specific solid-organ cancers associated with ARBs plus ACE inhibitor therapy, compared with ACE inhibitors alone. Cancer was a pre-specified endpoint of special interest in three of the five trials that included new cancer data for analysis of cancer occurrence (LIFE, ONTARGET and TRANSCEND).
In the ONTARGET and TRANSCEND trials, information on the occurrence of malignancies was also collected prospectively in more detail than usual for trials of cardiovascular outcomes, thereby placing the spotlight on telmisartan which was the study drug in 30 014 (85.7%) of the ARB-treated patients included in the meta-analysis. The association of ARBs with the occurrence of solid-organ cancers, new lung, prostate and breast cancer from the meta-analysis is summarised in Table 2.

Comment from Boehringer Ingelheim
Boehringer-Ingelheim commented that peer-reviewed meta-analyses of aggregate published data such as that of Sipahi et al. 1 have their appropriate place in scientific research. However, these publications have well-recognised limitations, including the following: • the analyses did not include the individual patient data for any of the trials • the trials were not designed to explore cancer outcomes • the adjudication of cancer diagnoses was not uniform among included studies • the analyses did not consider the latency for the malignancies • the analyses did not take into account the effect of gender, age, smoking or other known risk factors for malignancies. Boehringer-Ingelheim had conducted a comprehensive internal safety data analysis including malignancy data, which has formed part of the submission package to regulatory bodies since 2008. This analysis includes patient level time-to-event data, which are presented as malignancies per 100 patient years, and no statistically significant difference was observed.

Comment from Dr Carl Lombard on Boehringer-Ingelheim analysis
Systematic reviews, which evaluate different trials around the same question often lead to a formal pooled analysis of the relevant information through a metaanalysis. This is often a crude analysis since only the summarised data from trials are available from the publications.
The methodology of meta-analysis is well established and is a useful tool to pick up small signals of benefit or risk across trials with varying levels and direction of effect sizes. Sipahi et al. 1 utilised the meta-analysis methodology to look at the risk of solid-organ cancers in randomised, controlled trials of angiotensin receptor blockers. The conclusions reached from this analysis are balanced and qualified and clearly outline the limitations and need for further analysis.
Three of the trials involved in this analysis used the Boehringer-Ingelheim ARB, telmisarton. Boehringer-Ingelheim has provided additional information involving patient-level information on the incidence and progression of cancers in the study participants of these trials (Fig.  1, Table 3). 0 0 0 0 0 0 ∆ represents the difference between treatment arms: + occurred more frequently and -less frequently in telmisartan group; T = telmisartan, R = ramipril, P = placebo.
The information provided across the three trials is differential and limited, which does not allow an appropriate pooled analysis across them. For the TRANSCEND and ONTARGET trials for example, the patient years of follow up is absent, whereas it is provided for the PRoFESS trial. The report reviews the results of the three trials separately.
(telmisartan vs placebo), ONTARGET (telmisartan + ramipril, telmisartan vs ramipril)], the incidence rate ratio was 1.07; 95% CI: 0.99-1.14. 2. With background ACE inhibitor treatment [ONTARGET (telmisartan + ramipril vs ramipril)], the incidence rate ratio was 1.14; 95% CI: 1.03-1.16. 3. Without background ACE inhibitor treatment [PRoFESS (telmisartan vs placebo), TRANSCEND (telmisartan vs placebo), ONTARGET (telmisartan vs ramipril)], the incidence rate ratio was 1.03; 95% CI: 0.96-1.12. These analyses still have some limitations in that they utilise only patient follow up and do not adjust for latency and other confounders. However, the comparisons are between large groups of patients that have been properly randomised, and with the same intensity of follow up and malignancy ascertainment.
From analysis 3 in which monotherapy telmisartan was compared to either placebo or ramipril, there is no evidence of risk for overall malignancy with regard to this product. With regard to the telmisartan/ramipril combination arm, there is evidence of risk with regard to the incidence of overall malignancies.
The conclusion made by Boehringer-Ingelheim in their safety report is therefore objective: 'There was a modest imbalance in malignancies seen in some of the recently completed cardiovascular outcome studies with telmisartan. This imbalance was primarily in the telmisartan/ramipril combination arm in ONTARGET, as opposed to monotherapy arms of telmisartan vs rampipril.' However, the call for further analysis by Sipahi et al. 1 still stands, since the safety report of Boehringer-Ingelheim does not utilise the full potential of the available individual-level data for pooled analyses.

Comment from Dr Adam Nosworthy
The findings published by Sipahi et al. 1 in the 14 June issue of the Lancet raise the concern of most doctors involved in clinical trials. (1) Do the treatments intended to offer benefit result in long-term harm to patients? (2) The latest trend of regulatory bodies to grant fast-track approval to new medications needs to be carefully reviewed.
In an attempt to offer patients the latest Making approximate estimates for the patient years in TRANSCEND and ONTARGET from the information provided, and performing pooled analyses for overall malignancies, similar to that done by Sipahi et al.,  The most important tenant of clinical trials is to determine which statistical endpoints need to be defined prior to commencing any study, and any posthoc analysis needs to be treated with the contempt that it deserves. To group a number of studies involving the ARBs (meta-analysis) and to extrapolate that there is an increased incidence of cancer in certain groups of patients is bad medicine and the outcomes of this report should not influence the use of these agents in patients.
The analysis is contradictory -there is an increase in lung cancer, which is claimed to be statistically significant in the group of patients receiving ARBs, yet the incidence of other cancers is decreased or the same. The group of patients that would typically be enrolled in these studies is firstly, a group of patients that are high risk for lung cancer, as they no doubt include a skewed bias in favour of smokers. All these factors would need to be included in the statistical design of the study prior to drawing these conclusions.
At this stage, I can find no reason to be concerned about the use of ARBs in patients. Far more reliable prospective, randomised data need to be presented prior to considering withdrawing this class of drug from the market.
It is rather ironic that there is a concern regarding a slight increase in cancer incidence in patients using ARBs in a retrospective analysis of numerous studies, yet a medication that is used widely and is known to have far greater impact on the development of breast cancer in women is prescribed in far greater numbers on a daily basis by doctors around the worldoestrogen replacement therapy -without as much as a mention in widely read medical journals!